In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate is the most abundant neurotransmitter in the CNS, and mediates the major excitatory pathway in mammals. Glutamate is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are "ionotropic" excitatory amino acid receptors. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of a number of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions. Other neurological conditions, that are caused by glutamate dysfunction, require neuromodulation. These other neurological conditions include muscular spasms, migraine headaches, urinary incontinence, psychosis, opiate tolerance and withdrawal, anxiety, emesis, brain edema, chronic pain, convulsions, and tardive dyskinesia. The use of a neuroprotective agent, such as an NMDA receptor antagonist, is believed to be useful in treating these disorders and/or reducing the amount of neurological damage associated with these disorders. The excitatory amino acid antagonists are also useful as analgesic agents.
Recent studies have shown that NMDA receptor antagonists are neuroprotective in animal models of focal cerebral ischemia. Bullock and Fujisawa, Journal of Neurotrauma, 9 (supplement 2), S443 (1992); Scatton et al., Cerebrovascular Disease, 1, 121 (1991). These studies have shown that the competitive NMDA antagonist D-(-)CPP-ene provided protection in a focal cerebral ischemia model in cats, the competitive NMDA antagonist CGS 19755 provided protection in a focal cerebral ischemia model in rats, and the competitive NMDA antagonist LY233053 provided protection in a CNS ischemia model in rabbits. Bullock et al., Journal of Cerebral Blood Flow and Metabolism, 10, 668 (1990 ); Simon and Shirasho, Annals of Neurology, 27, 606 (1990 ); Madden et al., Journal of Neurosurgery, 76, 106 (1992). The non-competitive NMDA antagonist dizocilpine provided protection in models of focal cerebral ischemia in cats and rats. Park et al., Journal of Cerebral Blood Flow and Metabolism, 8, 757 (1988); Park et al., Annals of Neurology, 24, 543 (1988). The competitive NMDA antagonist LY274614 is neuroprotective in an animal model of Huntington's Disease. Schoepp, et al., Journal of Neural Transmission [General Section], 85, 131 (1991).
These studies strongly suggest that the delayed neuronal degeneration in brain ischemia involves glutamate excitotoxicity mediated at least in part by NMDA receptor activation. Thus, NMDA receptor antagonists will be useful as neuroprotective agents, decreasing the amount of glutamate-induced excitotoxicity and improving the neurological outcome of cerebral ischemia in humans.
Several studies have shown that NMDA antagonists are anticonvulsant agents. Meldrum, Epilepsy Research, 12, 189 (1992); Meldrum, Epilepsia, 32 (supplement 2), S1 (1991); Chapman and Meldrum, New Antiepileptic Drugs (Epilepsy Research Supplement 3), Elsevier, 39 (1991). For example, the competitive NMDA antagonists D-(-)CPP-ene and CGP 37849 are anticonvulsant against sound induced seizures in DBA/2 mice. Chapman, Graham, and Meldrum, European Journal of Pharmacology, 178, 97 (1990). Other studies have shown that NMDA antagonists are analgesics. For example, the competitive NMDA antagonist CGS 19755 is analgesic in a warm water tail withdrawal procedure in rhesus monkeys and the competitive NMDA antagonist DL-AP5 was analgesic in a mouse formalin model. France, Winger, and Woods, Brain Research, 526, 355 (1990); Murray, Cowan, and Larson, Pain, 44, 179 (1991).
Based on these animal models, NMDA receptor antagonists will be useful in treating acute and chronic neurodegenerative conditions, as well as other conditions that require neuromodulation.